Preliminary data from the FEM-PrEP trial show equal numbers of HIV infection in women taking Truvada as oral pre-exposure prophylaxis and those taking placebo.
A large trial of HIV pre-exposure prophylaxis (PrEP) has been stopped early, because it is “highly unlikely” to demonstrate that Truvada (tenofovir disoproxil fumarate/FTC) protects women against HIV infection.
In this phase III trial (called FEM-PrEP), 1951 HIV-negative, high-risk women in Africa were randomized to take Truvada or placebo orally once daily. All the women received monthly risk-reduction counseling, free condoms, and free treatment for sexually transmitted infections; they were also tested monthly for HIV infection and pregnancy.
Preliminary data from approximately 1100 person-years of follow-up indicate that 56 infections occurred during the trial, with exactly half in the Truvada group and half in the placebo group. This finding stands in stark contrast to the results of both the iPrEx trial, which showed a protective effect for once-daily oral Truvada among men who have sex with men, and the CAPRISA 004 trial, which showed a significant risk reduction among women who used a vaginal 1% tenofovir gel before and after sex. In both of those trials, the efficacy of PrEP was directly related to adherence. In the FEM-PrEP trial, preliminary data indicate that self-reported adherence levels were very high (around 95%) for visits where tablets were dispensed.
Another surprise finding in the FEM-PrEP study was a high pregnancy rate in the Truvada group compared with the placebo group. Nearly all participants (96%) were using hormonal contraceptives at study enrollment, raising questions about whether a previously unknown interaction might exist between these contraceptives and the antiretrovirals used in the study. Differential adherence to contraception might have also played a role, as indicated by the higher pregnancy rates seen among women who used oral versus injectable contraceptives.
Final, in-depth analyses of FEM-PrEP data will be conducted once follow-up is complete. In the meantime, several other PrEP trials are ongoing, with the VOICE trial being the most notable. In that study, 5000 women are being randomized to one of five study treatments, to be used daily: oral tenofovir, Truvada, oral placebo, tenofovir gel, or placebo gel.
Comment: While disappointing, the results of the FEM-PrEP trial are clear — they show zero effectiveness after 56 endpoints (75% of the target endpoints) were reached. The independent data monitoring committee determined that, under these circumstances, continuing the study to its target of 74 endpoints in an attempt to demonstrate Truvada’s efficacy would be futile. Why the trial did not produce positive results, as highly anticipated, is unclear. We do not yet know whether trial design and conduct (e.g., low adherence, tolerability) played a role in the findings, whether Truvada is ineffective at preventing HIV infection only in this study population, or whether it is generally ineffective in women. Detailed analyses from the trial, including data on drug levels in the blood and genital tract, are keenly awaited. Other, ongoing PrEP studies, which are being conducted in different populations with different approaches, might also provide valuable clues to interpreting the FEM-PrEP results.
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